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Polygenetics, Inc. |
Zero-Order Release
Published results show zero-order release is achieved when drugs are combined with Cavilink polymers. This release can be maintained within the therapeutic range for extended periods. In particular, release of actives contained in the microspheres can be set to 12 or 24 hours, ideal for oral administration. Several examples of Polygenetics’ technology for zero-order release follow.
NAPROSYN
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| Figure 1. Zero-order release of Naprosyn. Zero-order release is related to the geometry of the polymer and is independent of drug composition. Note the precision with which the release curve intersects the origin. This profile can be maintained for twenty-four hours, ideal for an anti-inflammatory drug. |
GUAIFENESIN
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| Figure 2. Zero-order release of Guaifenesin. Note how precisely the Cavilink combination product release profile passes through origin. This indicates nearly perfect zero-order with no initial burst that is common to many formulations. |
MUCINEXR VS. CAVILINKTM
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| Figure 3. Zero-order release of guaifenesin. There are clear pharmacological benefits to having constant release of an expectorant such as guaifenesin. This can be achieved with a Cavilink™ combination product (blue curve). Note that the commercial product (red curve) is exhausted after about seven hours. The initial burst associated with Mucinex® rises higher than necessary for pharmacological benefits. With a zero-order release profile, it is expected that the total dose required will be less than that required with a conventional immediate or sustained release product. |
GABAPENTIN-CAVILINK COMBINATION PRODUCT
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| Figure 4. Zero-order release of gabapentin. It is desirable to maintain constant blood levels of drugs used to treat both transitory and chronic pain. Note absence of burst, indicating nearly perfect zero-order profile. |
GABAPENTIN: CAVILINK VS. COMMERCIAL RX
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| Figure 5. Rate of release of gabapentin prescription drug (Alpharma) vs. Cavilink. The burst associated with Alpharma “sustained release” gabapentin exceeds desired therapeutic level (light blue line). Furthermore, overall release falls off dramatically after about six hours. Note that Cavilink combination product maintains constant release rate within therapeutic range over twenty-four hours (dark blue line). It is expected that the Cavilink combination product will require much lower dosage since it avoids bursts and the associated release of unnecessary amounts of drug. (Note: data points were omitted from the Cavilink plot to emphasize that the rate of release per hour can be moved up or down, as required. Cavilink data are from Figure 4.) |
Why Zero-Order?
Why do we obtain near zero-order release from these materials? Theory predicts near zero-order release can be obtained when cylinders are used to contain and release active ingredients. If an active is contained in a single cylinder such that it cannot escape through the walls, but only through the cylinder openings, release will be near zero-order because the opening has a fixed area. Release will not be exactly zero-order since it takes longer for ingredients contained in the center of the cylinder to elute compared with ingredients near the cylinder ends. However, if there are an infinite number of cylinders having different geometries, average release may approach zero-order. This is observed experimentally and we call this the “infinite cylinder” model.
This geometric microstructure is represented as groups of cylinders and compared with an SEM photograph of a single cavity of Cavilink. These are shown in below.
Zero-order release appears to be independent of drug composition and related only to geometry of Cavilink spheres. Thus whatever drug is contained in these microspheres will be released following near zero-order. Drugs can be acidic, basic, hydrophilic, hydrophobic, etc. and they will always be released following near zero-order since it is the physical structure of the microspheres that is responsible for the release profiles.
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Figure 6A. Grouping of cylinders showing fixed areas at openings. Drug release can only occur through this constant area and, in this model, drug cannot penetrate the walls of the cylinders. |
Figure 6B. High magnification of cavity structure of Cavilink polymer. Openings in each cavity connect to adjacent cavities. These openings correspond to the open ends of the cylinders in Figure 6A. The solid polymer wall corresponds to the walls of the cylinders shown in figure 6A. Ultimately, these fixed openings communicate with surface of polymer spheres. It is these fixed area openings that are responsible for the zero-order release characteristics of Cavilink. |
